Agonists of the A2A adenosine receptor (A2AAR) are known vasodilators that also inhibit inflammation at substantially lower doses. Activation of the A2AAR attenuates reperfusion injury after myocardial infarction (MI) by inhibiting leukocyte activation, endothelial adhesion and neutrophil accumulation. Not only is contractile function lost in the infarct zone as a result of MI, but recent evidence indicates that the cascade of cytokine elaboration initiated by MI also induces contractile dysfunction in remote zones of the left ventricle (LV) that were never made ischemic. We hypothesize that the anti-inflammatory properties of the A2AAR can be exploited to preserve contractile function early after large MI. We propose that whole animal experiments employing a complementary set of pharmacologic and genetic approaches will not only elucidate the anti-inflammatory role of A2AARs in this setting, but will also identify an effective treatment regimen. In preliminary studies, we have used a mouse model of reperfused MI and cardiac magnetic resonance imaging (MRI) to demonstrate that A2AAR activation markedly improves remote LV function on Day 1 after MI. In the proposed studies, the anti-inflammatory role of the A2AAR in remote LV dysfunction will be elucidated using specific pharmacologic agents, genetically-manipulated mice and bone marrow chimeras. A multidisciplinary approach will be used that spans the fields of immunology, radiology, cardiac physiology, pathology, cell biology and molecular genetics. The specific aims are to: 1) Elucidate the role of inflammation in remote LV dysfunction early after large MI. In preliminary studies, our lab has shown that a highly-selective agonist of the A2AAR (ATL146e) enhances contractile function in the remote LV on Day 1 post-MI. We hypothesize that the anti-inflammatory actions of A2AAR activation are responsible for this beneficial effect. 2) Determine the role of endogenous adenosine in remote zone LV dysfunction using A2AAR knock-out mice. We hypothesize that the activation of A2AAR by endogenous adenosine modulates contractile function in the remote LV early after MI. Thus remote zone LV dysfunction should be more severe in A2AAR knock-out mice than in congenic wild-types. 3) Determine the role of the myeloid lineage in remote zone LV dysfunction using bone marrow chimeras. We hypothesize that the beneficial effect of ATL146e on remote zone LV dysfunction is derived from its actions on myeloid cells. If so, transplantation of wild-type bone marrow into irradiated A2AAR knockout mice should restore the wild-type phenotype. 4) Define the impact of specific A2AAR activation on myocardial gene expression in the post-MI heart using transcriptional profiling. We hypothesize that the central importance of cytokine gene activation in remote LV dysfunction can be elucidated by comparing mRNA expression profiles from sham-operated, infarcted and ATL146e-treated hearts.